Breast cancer is a disease affecting a significant population of women around the world. About 1 in 8 women in the United States (between 12 and 13%) will develop invasive breast cancer over the course of her lifetime. Prognosis and survival rate varies greatly depending on cancer type and staging. Breast cancers expressing genetic characteristics such as human epidermal growth factor receptor-2 (HER2) are associated with a poor prognosis.
Research has focused on the use of recombinant humanized monoclonal antibodies for the treatment of cancers with cells that overexpress protein p185HER2. This 185-kDa growth factor receptor is encoded by the her-2 proto-oncogene, also referred to as neu and c-erbB-2 (Slamon et al. 1987 Science 235:177). The her-2 gene is closely related to the gene encoding epidermal growth factor receptor (EGFR). Amplification of the her-2 gene has been linked to neoplastic transformation in human breast cancer cells (Slamon et al. 1987 Science 235:177). Overexpression of the HER2 protein has been identified in 20-30% of breast cancer patients, and has been correlated with regionally advanced disease, increased probability of tumor recurrence, and reduced patient survival. As many as 30-40% of patients having gastric, endometrial, salivary gland, non-small cell lung, pancreatic, ovarian, peritoneal, prostate, or colorectal cancers may also exhibit overexpression of this protein.
A more difficult-to-treat form of HER2-negative breast cancer known as “triple-negative,” affects some patients. This form tests negative for three primary receptors: HER2, estrogen receptor and progesterone receptor. However, it is positive for epidermal growth factor receptor (EGFR, HER1).
Humanized anti-HER2/neu monoclonal antibody trastuzumab (Herceptin®, Genentech Inc., San Francisco, Calif.) is used alone or combined with chemotherapy for treatment of patients with advanced breast cancer overexpressing HER2/neu (Baselga J. 2006 Science 312:1175; Baselga J et al. 1999 Semin Oncol 26:78; Slamon D J et al. 2009 J Natl Cancer Inst 101:615), with significant anti-tumor effect. However, serious adverse effects on normal organs have been reported (Keef D L. 2002 Cancer 95:1592; Vahid B et al, 2008 Chest 133:528). Moreover, many patients develop resistance to Herceptin® within one year of treatment, which renders this treatment ineffective (Tseng P H et al. 2006 Mol Pharmacol 70:1534). Therefore, new drugs with minimal side effects for non-tumor tissues are urgently needed to improve HER2/neu-positive tumor therapy.